BAG6 negatively regulates the RLR signaling pathway by targeting VISA/MAVS

Abstract

The virus-induced signaling adaptor protein VISA (also known as MAVS, ISP-1, Cardif) is a critical adaptor protein in the innate immune response to RNA virus infection. Upon viral infection, VISA self-aggregates to form a sizeable prion-like complex and recruits downstream signal components for signal transduction. Here, we discover that BAG6 (BCL2-associated athanogene 6, formerly BAT3 or Scythe) is an essential negative regulator in the RIG-I-like receptor signaling pathway. BAG6 inhibits the aggregation of VISA by promoting the K48-linked ubiquitination and specifically attenuates the recruitment of TRAF2 by VISA to inhibit RLR signaling. The aggregation of VISA and the interaction of VISA and TRAF2 are enhanced in BAG6-deficient cell lines after viral infection, resulting in the enhanced transcription level of downstream antiviral genes. Our research shows that BAG6 is a critical regulating factor in RIG-I/VISA-mediated innate immune response by targeting VISA.

Deubiquitinase USP19 modulates apoptotic calcium release and endoplasmic reticulum stress by deubiquitinating BAG6 in triple negative breast cancer

“… 30 , 31 Furthermore, BAG6 could suppress RNA virus‐mediated innate immunity by increasing VISA/TRAF2 K48 poly‐ubiquitination. 32 Clearly, the upregulation of BAG6 greatly promoted BCL2 ubiquitination in MDA‐MB‐231 cells (Figure 6F ). A GST pull‐down assay in vitro was performed using the purified GST‐BAG6 and GST‐BCL2 proteins generated in E. coli BL21.…”

“…It was also involved in the regulation of apoptosis, antigen presentation and T‐cell response 30,31 . Furthermore, BAG6 could suppress RNA virus‐mediated innate immunity by increasing VISA/TRAF2 K48 poly‐ubiquitination 32 . Clearly, the upregulation of BAG6 greatly promoted BCL2 ubiquitination in MDA‐MB‐231 cells (Figure 6F).…”

BAG6 inhibits influenza A virus replication by inducing viral polymerase subunit PB2 degradation and perturbing RdRp complex assembly

“…Type I Interferon (IFN-I) plays a critical role in defending against viral infection and regulating innate immune response. A recent study reported that BAG6 was capable of regulating SeV-induced activation of IFN-I by inhibiting RIG-I/VISA-mediated innate immune response [ 29 ]. To assess the role of IFN-I pathway in BAG6-mediated anti-IAV response, we firstly examined the expressions of several key components involved in IFN-I signaling pathways, including pattern recognition receptor RIG-I, the phosphorylated STAT1 (P-STAT1) and the IFN-stimulated gene ISG15, in both BAG6 overexpressing and knocking-out HeLa cells during PR8 infection.…”

“…It promotes p53 transactivation by stabilizing its interaction with the acetyltransferase p300 and enhancing p53 acetylation during apoptosis and autophagy [ 21 , 22 , 53 ]. A recent study reported that BAG6 was capable of regulating the activation of IFN-I by inhibiting RIG-I/VISA-mediated recognition of RNA ligand [ 29 ]. However, the role of BAG6 in virus infection remains opaque.…”

Lung gene expression study identifying Zscan2 and Bag6 as novel tissue repair players in an experimental model of COPD

“…The exact role of Bag6 in the lung is not yet fully understood, but there is evidence to suggest that it may play a role in regulating in ammation and immune responses in the lung. Bag6 appears to be a negative regulator in the innate immune system of non-small cell lung cancer patients [36] [37] and a risk factor for lung cancer [38] [39], even in early non-smoker lung adenocarcinoma patients [40]. Germline variants of genes involved in nuclear factor-kappa B (NF-κB) activation are associated with the risk of developing COPD and lung cancer [41].…”